Since benzimidazole compounds such as lansoprazole, omeprazole, rabeprazole and the like have a proton pump inhibitor (hereinafter, abbreviated as ‘PPI’) like activity such as gastric acid secretion suppressing effect and gastric mucosa defensive effect, these compounds are used extensively as an agent for treatment of peptic ulcer disease and the like.
However, these compounds, in particular, amorphous benzimidazole compounds have a poor stability, and are unstable not only to temperature, humidity and light but also to water in solid state, which results in a terrible change in color etc. In particular, they are very unstable to acids and become extremely unstable in aqueous solution or suspension as the pH of the solution or suspension decreases.
In addition, as for the stability in a dosage form, namely, tablets, powders, fine granules, capsules, etc., compounds are more unstable than in compounds alone because there are strong interactions with these compounds and other ingredients in the formula of dosage form, and consequently, change in color or degradation is observed during manufacturing and storage. In order to stabilize these compounds, for example, JP-A 62-277322 discloses enteric coating granules or enteric coating fine granules after blending some stabilizers namely, basic inorganic salt of magnesium and/or calcium.
Since benzimidazole compounds having a PPI activity have generally a property of hard to dissolve in water and are unstable in acids, an enteric coating is needed to be applied to them. An enteric coating layer is applied expecting that a benzimidazole compounds are not dissolved in the stomach having a low pH value and comparatively much water, but are dissolved and absorbed in the small intestine having a high pH value and less water. However, a document that discloses specifically about studies on the stabilization of a preparation containing an amorphous benzimidazole compound, which is unstable to atmospheric moisture as well as to acids, has not been reported.
Furthermore, a solution, suspension, tablet and capsule obtained by combining omeprazole or lansoprazole, which is not enteric-coated, with an alkali metal salt of bicarbonate are disclosed in U.S. Pat. No. 5,840,737 and WO 00/26185.
However, since these dosage forms are combination dosage forms with compounds and a bicarbonate, the bicarbonate reacts with gastric acid, and carbon dioxide is generated. This gas causes burping, therefore they are not preferred with a viewpoint of compliance.